This invention concerns novel heterocyclic compounds which antagonize the pharmacological actions of one of the endogenous neuropeptide tachykinins known as neurokinins, particularly at the neurokinin 2 (NK2) receptor. The novel heterocyclic compounds are useful whenever such antagonism is desired. Thus, such compounds may be of value in the treatment of those diseases in which an NK2 receptor is implicated, for example, in the treatment of asthma and related conditions. The invention also provides pharmaceutical compositions containing the novel heterocyclic compounds for use in such treatment, methods for their use, and processes and intermediates for the manufacture of the novel heterocyclic compounds.
The mammalian neurokinins comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems. The three principal neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB). There are also N-terminally extended forms of at least NKA. At least three receptor types are known for the three principal neurokinins. Based upon their relative selectivities favoring the neurokinin agonists SP, NKA and NKB, respectively, the receptors are classifed as neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3) receptors, respectively. In the periphery, SP and NKA are localized in C-afferent sensory neurons, which neurons are characterized by non-myelinated nerve endings known as C-fibers, and are released by selective depolarization of these neurons, or selective stimulation of the C-fibers. C-Fibers are located in the airway epithelium, and the tachykinins are known to cause profound effects which clearly parallel many of the symptoms observed in asthmatics. The effects of release or introduction of tachykinins in mammalian airways include bronchoconstriction, increased microvascular permeability, vasodilation and activation of mast cells. Thus, the tachykinins are implicated in the pathophysiology and the airway hyperresponsiveness observed in asthmatics; and blockade of the action of released tachykinins may be useful in the treatment of asthma and related conditions. Peptidic NK2 antagonists have been reported. For example, a cyclic hexapeptide known as L-659,877 has been reported as a selective NK2 antagonist. Nonpeptidic tachykinin antagonists have been reported, for example in European Patent Application, Publication Number (EPA) 428434, EPA 474561, EPA 512901, EPA 512902, EPA 515240 and EPA 559538, as well as in WO 94/10146, EPA 0625509, EPA 0630887, WO 95/05377, WO 95/12577, WO 95/15961, EPA 680962, and WO 95/16682.
We have discovered a series of nonpeptidic NK2 antagonists, and this is the basis for our invention.
According to the invention, there is provided a Compound of the invention which is a compound of formula I (formula set out hereinbelow following the Examples, together with other formulae denoted by Roman numerals) wherein
Q1 is a radical (attached at Z) selected from the group of radicals of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik and Im, wherein
for a radical of formula Ia, Za is nitrogen or a group CRad in which Rad is hydrogen or Rad together with Rac and the existing carbon to carbon bond forms a double bond; Raa is Ar or Het; Rab is hydrogen and Rac is hydrogen or hydroxy or Rac together with Rad and the existing carbon to carbon bond forms a double bond, or Rac and Rad together form a diradical xe2x80x94(CH2)jxe2x80x94 in which j is an integer from 1 to 5; or Rab and Rac together form a diradical xe2x80x94(CH2)kxe2x80x94 in which k is an integer from 2 to 6, or Rab and Rac together are oxo or dialkylaminoalkyloxyimino of formula xe2x95x90Nxe2x80x94Oxe2x80x94(CH2)qxe2x80x94NRaeRaf in which q is the integer 2 or 3 and Rae and Raf are independently hydrogen or (1-4C)alkyl, or the radical NRaeRaf is pyrrolidino, piperidino or morpholino;
for a radical of formula Ib, Zb is a substituted imino group RbaN or RbaCH2N in which Rba is (3-7C)cycloakyl, Ar or Het; or Zb is a disubstituted methylene group Rbb(CH2)pxe2x80x94Cxe2x80x94Rbc in which Rbb is Ar or Het; p is the integer 0 or 1; and Rbc is hydrogen, hydroxy, (1-4C)alkoxy, (1-4C)alkanoyloxy, COORbd (wherein Rbd is hydrogen or (1-3C)alkyl), cyano, NRbeRbf or SRbg in which Rbe and Rbf are independently hydrogen, (1-4C)alkyl, (1-4C)hydroxyalkyl or (1-4C)alkanoyl, or the radical NRbeRbf is pyrrolidino, piperidino or morpholino; and Rbg is hydrogen or (1-4C)alkyl; or Rbc forms a double bond with the carbon atom to which it is bonded and with the adjacent carbon atom in the piperidine ring;
for a radical of formula Ic, Rca is Ar or Het; and Zc is oxo, thio, sulfinyl, sulfonyl or imino of formula xe2x80x94NRcbxe2x80x94 in which Rcb is (1-3C)alkyl or RccRcdNxe2x80x94(CH2)qxe2x80x94 in which q is the integer 2 or 3 and in which Rcc and Rcd are independently hydrogen or (1-3C)alkyl or the radical RccRcdN is pyrrolidino, piperidino or morpholino;
for a radical of formula Id, Rda is hydrogen, (1-6C)alkyl, Ar, Het, xcex1-hydroxybenzyl, styryl, or Rdbxe2x80x94(1-3C)alkyl in which Rdb is aryl, pyridyl, pyridylthio or 1-methyl-2-imidazolylthio in which an aromatic group or portion of Rda may bear one or more halo, hydroxy, (1-4C)alkyl or (1-4C)alkoxy substituents; Xd is oxy or xe2x80x94CHRdcxe2x80x94; Rdc is hydrogen, hydroxy, (1-3C)alkoxy, (1-4C)alkanoyloxy, NRddRde or (1-4C)alkanoylamino; Rdd and Rde are independently hydrogen or (1-4C)alkyl or the radical NRddRde is pyrrolidino, piperidino or morpholino; p is the integer 0 or 1; and Zd is a single bond (except when Rda is hydrogen or p is 1), methylene or carbonyl;
for a radical of formula Ie, Je is oxygen, sulfur or NRea in which Rea is hydrogen or (1-3C)alkyl; Reb is hydrogen, (1-6C)alkyl which may bear a hydroxy substituent and/or one to three fluoro substituents, (3-6C)alkenyl (in which a vinyl carbon is not bound to nitrogen), 2-hydroxyethyl, (3-7C)cyloalkyl, Ar or Het; Rec is hydrogen, (1-6C)alkyl which may bear a hydroxy substituent and/or one to three fluoro substituents, (3-6C)cycloalkyl, (1-5C)alkoxy (only when Je is oxygen), (3-6C)cycloalkoxy (only when Je is oxygen), or an amino group of formula NRedRee containing zero to seven carbon atoms in which each of Red and Ree is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NRedRee is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl group may bear a (1-3C)alkyl substituent at the 4-position);
for a radical of formula If, Jf is oxygen, sulfur or NRfa in which Rfa is hydrogen or (1-3C)alkyl; Lf is a divalent hydrocarbon group in which the 1-position is bound to the carbon bearing the group Jf, the divalent group Lf being selected from trimethylene, cis-propenylene, tetramethylene, cis-butenylene, cis-but-3-enylene, cis,cis-butadienylene, pentamethylene and cis-pentenylene which divalent group Lf itself may bear one or two methyl substituents;
for a radical of formula Ig, Zg is (1-8C)alkyl or (3-8C)cycloalkyl which may bear one or more substituents selected from the group consisting of halo, (3-6C)cycloalkyl, cyano, nitro, hydroxy, (1-4C)alkoxy, (1-5C)alkanoyloxy, aroyl, heteroaroyl, oxo, imino (which may bear a (1-6C)alkyl, (3-6C)cycloalkyl, (1-5C)alkanoyl or aroyl substituent), hydroxyimino (which hydroxyimino may bear a (1-4C)alkyl or a phenyl substituent on the oxygen), an amino group of formula NRgaRgb, an amino group of formula NRgcRgd, an amidino group of formula C(xe2x95x90NRgg)NRgeRgf, and a carbamoyl group of formula CON(ORgh)Rgi, but excluding any radical wherein a hydroxy and an oxo substituent together form a carboxy group, wherein an amino group of formula NRgaRgb contains zero to seven carbon atoms and each of Rga and Rgb is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NRgaRgb is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent group at the 4-position); and wherein Rgc is hydrogen or (1-3C)alkyl and Rgd is (1-5C)alkanoyl, aroyl or heteroaroyl; or Rgd is a group of formula C(xe2x95x90Jg)NRgeRgf in which Jg is oxygen, sulfur, NRgg or CHRgj; and wherein the amino group NRgeRgf contains zero to seven carbon atoms and each of Rge and Rgf is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NRgeRgf is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position) or Rge is hydrogen or (1-4C)alkyl and Rgf together with Rgg forms an ethylene or trimethylene group; Rgg is hydrogen, (1-4C)alkyl or together with Rgf forms an ethylene or trimethylene group; Rgj is cyano, nitro or SO2Rgk and Rgk is (1-4C)alkyl or phenyl; Rgh and Rgi are independently (1-3C)alkyl; and in which a cyclic group which is a substituent on Zg or formed by substitution on Zg may bear one or more (1-3C)alkyl groups on carbon as further substituents; and in which any aryl or heteroaryl group which is a part of the group Zg may bear one or more halo, (1-4C)alkyl, (1-4C)alkoxy, cyano, trifluoromethyl or nitro substituents;
for a radical of formula Ih, Gh denotes a single bond, a double bond or a divalent hydrocarbon radical; Jh denotes a radical joined to the ring by a single bond if Gh denotes a double bond or, otherwise, a radical joined by a double bond; Mh denotes a heteroatom a substituted heteroatom, or a single bond; and Lh denotes a hydrocarbon radical in which the 1-position is attached to Mh; wherein the values of Gh, Jh, Mh and Lh are selected from
(a) Gh is a single bond; Jh is oxo or thioxo; Mh is oxy, thio or NRha; and Lh is Lha;
(b) Gh is a single bond; Jh is NRhb; Mh is NRha; and Lh is Lha;
(c) Gh is a double bond, Jh is ORha, SRha or NRhcRhd; Mh is nitrogen; and Lh is Lha;
(d) Gh is methylene which may bear one or two methyl substituents; Jh is oxo, thio or NRhe; Mh is oxy, thio, sulfinyl, sulfonyl or NRha; and Lh is Lhb;
(e) Gh is a single bond; Jh is oxo, thioxo or NRhe; Mh is nitrogen; and Lh is Lhc;
(f) Gh is methine, which may bear a (1-3C)alkyl substituent; Jh is oxo, thioxo or NRhe; Mh is nitrogen; and Lh is Lhd; (g) Gh is cis-vinylene, which may bear one or two methyl substituents; Jh is oxo, thioxo, or NRhe; Mh is nitrogen; and Lh is Lhe; and
(h) Gh is a single bond; Jh is oxo or thioxo; Mh is a single bond; and Lh is Lhf; wherein
Rha is hydrogen or (1-3C)alkyl; Rhb is hydrogen, (1-3C)alkyl, cyano, (1-3C)alkylsulfonyl or nitro; Rhc and Rhd are independently hydrogen or (1-3C)alkyl or the radical NRhcRhd is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position); Rhe is hydrogen or (1-3C)alkyl; Lha is ethylene, cis-vinylene, trimethylene or tetramethylene which radical Lha itself may bear one or two methyl substituents; Lhb is ethylene or trimethylene which radical Lhb itself may bear one or two methyl substituents; Lhc is prop-2-en-1-yliden-3-yl, which radical Lhc itself may bear one or two methyl substituents; Lhd is cis-vinylene, which radical Lhd itself may bear one or two methyl substituents; Lhe is methine, which radical Lhe itself may bear a (1-3C)alkyl substituent; and Lhf is 4-oxabutan-1,4-diyl;
for a radical of formula Ij, Xj is (1-6C)alkyl, xe2x80x94CH2ORja, xe2x80x94CH2SRja, xe2x80x94CH2S(O)Rjg, xe2x80x94CH2S(O)2Rjg, xe2x80x94CORja, xe2x80x94COORja, xe2x80x94C(xe2x95x90Jja)NRjbRjc, xe2x80x94C(Rja)(ORjd)(ORje), xe2x80x94CH2N(Rja)C(xe2x95x90Jja)Rjf, xe2x80x94CH2N(Rja)COORjg or xe2x80x94CH2N(Rja)C(xe2x95x90Jja)NRjbRjc; Bj is a direct bond and Lj is a hydrocarbon chain in which the 1-position is bound to Bj and Lj is selected from trimethylene, tetramethylene, cis-1-butenylene and cis,cis-butadienylene; or Bj is N(Rjh) and Lj is a hydrocarbon chain selected from ethylene, trimethylene and cis-vinylene; or Bj is N and Lj is a hydrocarbon chain in which the 1-position is bound to Bj and Lj is cis,cis-prop-2-en-1-ylidin-3-yl; Jj and Jja are independently oxygen or sulfur; Rja, Rjf and Rjh are independently hydrogen or (1-6C)alkyl; Rjb and Rjc are independently hydrogen or (1-6C)alkyl; or the radical NRjbRjc is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position); Rjd and Rje are independently (1 -3C)alkyl or together form a divalent hydrocarbon chain selected from ethylene and trimethylene; Rjg is (1-6C)alkyl;
for a radical of formula Ik, Zk is a nitrogen linked radical of formula II wherein E1, E2, E3 and E4 form a divalent four membered chain (xe2x80x94E1xe2x95x90E2xe2x80x94E3xe2x95x90E4xe2x80x94) in which each of E1, E2, E3 and E4 is methine; or in which one or two of E1, E2, E3 and E4 is nitrogen and the remaining E1, E2, E3 and E4 are methine; and further wherein one or more of E1, E2, E3 and E4 which is methine may bear a halo, (1-3C)alkyl, hydroxy, (1-3C)alkoxy, (1-3C)alkylthio, (1-3C)alkylsulfinyl or (1-3C)alkylsulfonyl substituent; and wherein the radicals Fk, Gk, and Ik(Xk) are selected from
(a) Gk is a direct bond, Ik(Xk) is a radical having the formula xe2x95x90C(Zk)xe2x80x94 and Fk is a radical selected from xe2x80x94CHxe2x95x90 and xe2x80x94Nxe2x95x90;
(b) Gk is a direct bond, Ik(Xk) is a radical having the formula xe2x80x94C(xe2x95x90Jk)xe2x80x94 and Fk is a radical selected from xe2x80x94N(Rkf)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94N(Rkf)xe2x80x94 and xe2x80x94CHxe2x95x90Nxe2x80x94;
(c) Gk is a radical having the formula xe2x80x94CH2xe2x80x94, Ik(Xk) is a radical having formula xe2x80x94C(xe2x95x90Jk)xe2x80x94 and Fk is selected from xe2x80x94CH2xe2x80x94 and xe2x80x94N(Rkf)xe2x80x94; and
(d) Gk is selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94Nxe2x95x90CHxe2x80x94, Ik(Xk) is a radical having the formula xe2x80x94C(xe2x95x90Jk)xe2x80x94 and Fk is a direct bond; wherein
Jk is oxygen or sulfur; Zk is xe2x80x94ORka, xe2x80x94SRka, xe2x80x94CORka, xe2x80x94COORka, xe2x80x94C(xe2x95x90Jka)NRkbRkc or xe2x80x94C(Rka)(ORkd)(ORke); Jka is oxygen or sulfur; Rka and Rkf are independently hydrogen or (1-6C)alkyl; Rkb and Rkc are independently hydrogen or (1-6C)alkyl; or the radical NRkbRkc is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position); Rkd and Rke are independently (1-3C)alkyl or Rkd and Rke together form ethylene or trimethylene; or Zk is an imido radical selected from phthalimido, succinimido, maleimido, glutarimido, and 3-oxa-, 3-thia- and 3-azaglutarimido, in which the imido radical may bear one or more (1-3C)alkyl substituents and, in addition, the aromatic portion of the phthalimido may bear one or more halo, hydroxy or (1-3C)alkoxy substituents; and
for a radical of formula Im, Rma and Rmb are independantly selected from the group consisting of hydrogen, (1-3C)alkyl, benzyl, and phenethyl; and Rmc is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position); and wherein
for a radical Q1, Ar is a phenyl radical or an ortho-fused bicyclic carbocyclic radical of nine of ten ring atoms in which at least one ring is aromatic, which radical Ar may be unsubstituted or may bear one or more substituents selected from halo, cyano, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, methylenedioxy, hydroxy, mercapto, xe2x80x94S(O)nRxa, (1-5C)alkanoyl, (1-5C)alkanoyloxy, nitro, NRxbRxc, NRxdRxe, C(xe2x95x90NRxf)NRxgRxh, CONRxbRxc and COORxj wherein n is the integer 0, 1, or 2; Rxa is (1-6C)alkyl, (3-6C)cycloalkyl or phenyl (which phenyl may bear a halo, trifluoromethyl, (1-3C)alkyl or (1-3C)alkoxy substitutent); the radical NRxbRxc contains zero to seven carbons and each of Rxb and Rxc is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NRxbRxc is pyrrolidino, piperidino, morpholino, thiomorpholine (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position); and wherein Rxd is hydrogen or (1-4C)alkyl and Rxe is (1-5C)alkanoyl, benzoyl; or a group of formula C(xe2x95x90Jx)NRxgRxh in which Jx is oxygen, sulfur, NRxf or CHRxi; Rxf is hydrogen, (1-5C)alkyl or together with Rxg forms an ethylene or trimethylene diradical, the radical NRxgRxh contains zero to 7 carbons and each of Rxg and Rxh is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NRxgRxh is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the 4-position); or Rxg together with Rxf forms an ethylene or trimethylene diradical and Rxh is hydrogen or (1-5C)alkyl; Rxi is cyano, nitro, (1-5C)alkylsulfonyl or phenylsulfonyl; and Rxj is hydrogen, (1-5C)alkyl or benzyl; and Het is a radical (or stable N-oxide thereof) attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms selected from oxygen, sulfur and nitrogen, or an ortho-fused bicyclic heterocycle derived therefrom by fusing a propenylene, trimethylene, tetramethylene or benz-diradical, which radical Het may be unsubstituted or may be substituted on carbon by one or more of the substituents defined above for Ar and may be substituted on nitrogen by (1-3C)alkyl;
Q2 is a nitrogen-linked five-membered aromatic ring containing 1-4 nitrogens, which is substituted at a ring position adjacent to the nitrogen-link by a group Q5;
Q3 is hydrogen or (1-3C)alkyl;
Q4 is phenyl which may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl and methylenedioxy; or Q4 is thienyl, imidazolyl, benzo[b]thiophenyl or naphthyl any of which may bear a halo substituent; or Q4 is biphenylyl; or Q4 is carbon-linked indolyl which may bear a benzyl substituent at the 1-position; and
Q5 is selected from the group consisting of phenyl, benzyl, phenethyl and naphthyl, wherein any phenyl ring or naphthyl may bear one or more substituents selected from (1-3C)alkyl, (1-3C)alkoxy, methylenedioxy, halogeno, hydroxy, (1-4C)acyloxy and NRARB in which RA and RB are independently hydrogen or (1-3C)alkyl, or RA is hydrogen or (1-3C)alkyl and RB is (1-4C)acyl;
or the N-oxide of a piperidino nitrogen indicated by xcex94 (or of either basic piperazinyl nitrogen of Q1 when Za is nitrogen);
or a pharmaceutically acceptable salt thereof;
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by xcex94 (or either basic piperazinyl nitrogen of Q1 when Za is nitrogen) is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.
A subgroup of the invention is a compound of formula III, or a pharmaceutically acceptable salt thereof, wherein Q1, Q2, and Q5 have any of the meanings given above for a compound of formula I.
It will be appreciated that a compound of formula I (or III) contains one or more asymmetrically substituted carbon atoms such that such a compound may be isolated in optically active, racemic and/or diastereomeric forms. A compound may exhibit tautomerization. A compound may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, diastereomeric, tautomeric, polymorphic or stereoisomeric form, or mixture thereof, which form possesses NK2 antagonist properties, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form or by synthesis from optically-active starting materials) and how to determine the NK2 antagonist properties by the standard tests described hereinafter. It may be preferred to use the compound of formula I (or III) in an optically pure form which is characterized as containing, for example, at least 95%, 98% or 99% enantiomeric excess of a particular form. For example, it may be preferred to use the compound of formula I (or III), or a particular diastereomer thereof, in a form which is characterized as containing at least 95%, 98% or 99% enantiomeric excess of the form with the (S)-configuration at the center indicated by * in the formulae.
In this specification Raa, Rab, R1, R2, et cetera stand for generic radicals and have no other significance. It is to be understood that the generic term xe2x80x9c(1-6C)alkylxe2x80x9d includes both straight and branched chain alkyl radicals but references to individual alkyl radicals such as xe2x80x9cpropylxe2x80x9d embrace only the straight chain (xe2x80x9cnormalxe2x80x9d) radical, branched chain isomers such as xe2x80x9cisopropylxe2x80x9d being referred to specifically. A similar convention applies to other generic groups, for example, alkoxy, alkanoyl, et cetera. Halo is fluoro, chloro, bromo or iodo. Aryl (except where more specifically defined) denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl (except where more specifically defined) encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five ring atoms consisting of carbon and one to four heteroatoms selected from oxygen, sulfur and nitrogen or containing six ring atoms consisting of carbon and one or two nitrogens, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propenylene, trimethylene of tetramethylene diradical thereto, as well as a stable N-oxide thereof. Aroyl is arylcarbonyl; heteroaroyl is heteroarylcarbonyl.
A pharmaceutically acceptable salt is one made with an acid which provides a physiologically acceptable anion.
Particular values are listed below for radicals or portions thereof (for example, particular values for (1-3C)alkyl provide particular values for the alkyl portion of (1-3C)alkoxy or (1-3C)alkylsulfinyl), substituents and ranges for a compound of formula I or formula III as described above for illustration only and they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
A particular value for Ar is phenyl which may be unsubstituted or may bear a chloro, methyl, methoxy, hydroxy or methylsulfinyl substituent. A particular value for Het is furyl, thienyl, 2-imidazolyl, 1,3,4-oxadiazol-2-yl, pyridyl or pyrimidinyl which ring may be unsubstituted or may bear a chloro, methyl, methoxy, hydroxy, methylsulfinyl, methoxycarbonyl or ethoxycarbonyl substituent. A particular value for aryl is phenyl. A particular value for heteroaryl is furyl, pyridyl or pyrimidinyl. A particular value for halo is chloro or bromo. A particular value for (1-3C)alkyl is methyl, ethyl, propyl or isopropyl; for (1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; for (1-5C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or isopentyl; for (1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or isohexyl; and for (1-8C)alkyl is methyl, ethyl, propyl, isopropyl, isopentyl, 1-ethylpropyl, hexyl, isohexyl, 1-propylbutyl, or octyl. A particular value for (3-6C)cylcoalkyl is cyclopropyl, cyclopentyl or cyclohexyl; for (3-7C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl; and for (3-8C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. A particular value for (3-6C)alkenyl is allyl, 2-butenyl or 3-methyl-2-butenyl. A particular value for (1-4C)alkanoyl is formyl, acetyl, propionyl, butyryl or isobutyryl; and for (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl.
A more particular value for Ar is phenyl which may be unsubstituted or may bear a methoxy, hydroxy or methylsulfinyl substituent. A more particular value for Het is pyridyl or pyrimidinyl which ring may be unsubstituted or may bear a methoxy, hydroxy or methylsulfinyl substituent. A more particular value for heteroaryl is pyridyl. A more particular value for halo is chloro. A more particular value for (1-3C)alkyl is methyl; for (1-4C)alkyl is methyl or ethyl; for (1-5C)alkyl is methyl, ethyl, propyl or isopropyl; for (1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; and for (1-8C)alkyl is methyl, ethyl, propyl, isopropyl, 1-ethylpropyl or 1-propylbutyl. A more particular value for (3-6C)cylcoalkyl is cyclopropyl or cyclopentyl; for (3-7C)cycloalkyl is cyclopropyl or cyclopentyl; and for (3-8C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. A more particular value for (3-6C)alkenyl is allyl. A more particular value for (1-4C)alkanoyl is formyl or acetyl; and for (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl or isobutyryl.
A particular value for Q1 is 4-benzylpiperidino, 4-(3-methoxyphenyl)piperidino, 4-(2-methylsulfinyl)phenylpiperidino, 4-(2-pyridyl)piperidino, 4-(3-pyridyl)piperidino, 4-(2-methylsulfinylpyrid-3-ylpiperidino, 4-hydroxy-4-phenylpiperidino, 4-acetamido-4-phenylpiperidino, 4-(N-phenylacetamido)piperidino, 4-(2-hydroxyethyl)piperidino, 4-(1-hydroxy-1-propylbutyl)piperidino, 4-(2-oxopyrrolidin-1-yl)piperidino, 4-(2-oxopiperidino)piperidino, 4-(2-thioxopiperidino)piperidino, 4-(2-oxoperhydropyrinmidin-1 -yl)piperidino, 4-ethoxycarbonyl-4-(2-oxopiperidino)piperidino, 4-methoxycarbonyl-4-(2-oxoperhydropyrimidin-1-yl)piperidino, 4-(1-oxoisoindolin-2-yl)piperidino, 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidino, 4-(2-oxo-1,2,3,4-tetrahydroquinazolin-3-yl)piperidino 4-methylaminocarbonyl-4-(2-oxopiperidino)piperidino, 4-aminocarbonyl-4-(piperidino)piperidino, 4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidino, 4-(3-ethyl-2-oxoperhydropyrimidin-1-yl)piperidino, 4-(N,N-dimethylaminocarbonyl)-4-(2-oxopiperidino)piperidino, 4-methyl-4-(2-oxoperhydropyrimidin-1-yl)piperidino, 4-methyl-4-(2-oxoperhydropyrimnidin-1-yl)piperidino, 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidino, 4-(2-oxoperhydropyrimidin-1-yl)-4-(pyrrolidin-1-ylcarbonyl)piperidino, 4-(5,5-dimethyl-2-oxoperhydropyrimnidin-1-yl)piperidino, or 4-methyl-4-(2-oxopiperidino)piperidino.
A particular value for Q2 is tetrazol-1-yl, imidazol-1-yl, or 1,3,4-triazol-1-yl.
A particular value for Q3 is hydrogen.
A particular value for Q4 is 3,4-dichlorophenyl or 3,4-methylenedioxyphenyl.
A particular value for R1 is methyl or benzyl and for A is, for example, chloride, bromide or methanesulfonate.
A more particular value for Q1 is 4-hydroxy-4-phenylpiperidino, 4-(2-oxopyrrolidin-1-yl)piperidino, 4-acetamido-4-phenylpiperidino, 4-acetamido-4-(2-oxopiperidino)piperidino, 4-ethoxycarbonyl-4-(2-oxopiperidino)piperidino, 4-methoxycarbonyl-4-(2-oxopiperidino)piperidino, 4-methylaminocarbonyl-4-(2-oxopiperidino)piperidino, 4-(dimethylamino)carbonyl-4-(2-oxopiperidino)piperidino, 4-aminocarbonyl-4-(piperidino)piperidino, 4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidino, 4-(3-ethyl-2-oxoperhydropyrimidin-1-yl)piperidino, 4-methyl-4-(2-oxopiperidino)piperidino, 4-methyl-4-(2-oxoperhydropyrimidin-1-yl)piperidino, 4-(2-oxo-2,3 -dihydrobenzimidazol-1-yl)piperidino, 4-(2-oxoperhydropyrimidin-1-yl)-4-(pyrrolidin-1-ylcarbonyl)piperidino, or 4-(5,5-dimethyl-2-oxoperhydropyrimidin-1-yl)piperidino.
A more particular value for Q2 is imidazol-1-yl.
A particular group of compounds of formula I (or formula III) is one in which Q1 is selected from a radical of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik or Im; or a pharmaceutically acceptable salt thereof.
A particular group of compounds of formula I (or formula III) is one in which Q1 is selected from a combination of the radicals of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, and Im; or a pharmaceutically acceptable salt thereof.
A particular group of compounds of formula I is one in which Je, Jf, Jg, Jj, Jja, Jk and Jka are oxygen and Jh is oxo; Q2 represents one of the more particular values listed above for Q2; Q3 is hydrogen; Q4 is phenyl which may bear one or two substituents selected from halo, trifluoromethyl and methylenedioxy; and Q5 is phenyl; or a pharmaceutically acceptable salt thereof.
A more particular group of compounds of formula I is one in which Q1 is a radical of of formula If, Ih or, Ij and wherein J is oxygen and in which the radicals and substituents may have any of the values, particular values or more particular values defined above; or a pharmaceutically acceptable salt thereof.
For compounds of the invention that include groups which may be substituted by xe2x80x9cone or morexe2x80x9d substituents as defined above, the term xe2x80x9cone or morexe2x80x9d may preferably be 1, 2, 3, or 4.
Specific compounds of formula I (and of formula III) are described in the accompanying Examples.
Pharmaceutically acceptable salts of a compound of formula I (or of formula III) include those made with a strong inorganic or organic acid which affords a physiologically acceptable anion, such as, for example, hydrochloric, sulfuric, phosphoric, methanesulfonic, or para-toluenesulfonic acid.
A compound of formula I (or of formula III) may be made by processes which include processes known in the chemical art for the production of structurally analogous heterocyclic compounds. Such processes and intermediates for the manufacture of a compound of formula I (or of formula III) as defined above are provided as further features of the invention and are illustrated by the following procedures in which the meanings of generic radicals are as defined above unless otherwise indicated:
(a) For a compound of formula I in which Z denotes a nitrogen (or for a compound of formula III), alkylating a piperidine of formula IIIa (wherein Q1a is a radical of formula Q1 defined above for a compound of formula I in which Z denotes a nitrogen) with an aldehyde of formula IV, by reductive alkylation. The alkylation is preferably carried out by a conventional reductive alkylation, for example as described in Example 1, by the in situ, acid-catalyzed formation of an imminum salt, followed by reduction with sodium cyanoborohydride in alcoholic solvent.
(b) Alkylating a piperidine of formula IIIa with an alkylating agent of formula V in which Y is a leaving group. Typical values for Y include for example, iodide, bromide, methanesulfonate, p-toluenesulfonate, trifluoromethane-sulfonate, and the like. The reaction may be carried out under standard conditions, for example in a suitable solvent at a temperature in the range of xe2x88x9220 to 100xc2x0 C., preferably in the range of 0 to 50xc2x0 C.
(c) For an N-oxide of the piperidino nitrogen indicated by xcex94 in a compound of formula I (or of formula III), oxidizing the piperidino nitrogen indicated by xcex94 in a corresponding compound of formula I using a conventional procedure, such as, for example, using hydrogen peroxide in methanol, peracetic acid, 3-chloroperoxybenzoic acid in an inert solvent (such as dichloromethane) or dioxirane in acetone.
(d) For a quaternary ammonium salt of the piperidino nitrogen indicated by xcex94 in a compound of formula I (or of formula III), alkylating the piperidino nitrogen indicated by xcex94 in a compound of formula I (or of formula III) with an alkylating agent of formula R1Y or alkylating a piperidine of formula IIIb with an alkylating agent of formula V, wherein Y is a leaving group, followed, if required, by exchanging the counterion Y for a different counterion A by a conventional method. Typical values for Y include those listed above. Exchange of counterions may conveniently be carried out using a basic ion exchange resin in the xe2x80x9cAxe2x80x9d form.
(e) For a compound of formula I in which Q1 is of formula Id, reducing the double bond of a corresponding starting material of formula VI using a conventional method.
(f) For a compound of formula I in which Q1 is of formula Id, substituting the nitrogen of a compound of formula VIa with a radical of formula Rdaxe2x80x94(Xd)pxe2x80x94Zdxe2x80x94 using a conventional method.
(g) For a compound of formula I (or of formula III) which bears a sulfinyl group, oxidizing the sulfur of a corresponding compound of formula I (or of formula III) which bears a sulfide group using a conventional method.
(h) For a compound of formula I (or of formula III) which bears a sulfonyl group, oxidizing a sulfide or sulfinyl group of a corresponding compound of formula I (or of formula III) using a conventional method.
(i) For a compound of formula I (or of formula III) which bears an aromatic hydroxy group, cleaving the ether of a corresponding compound of formula I (or of formula III) which bears an aromatic alkoxy group using a conventional method.
It may be desired to optionally use a protecting group during all or portions of the above described processes; the protecting group then may be removed when the final compound is to be formed.
Whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of formula I is required, it may be obtained by reacting the compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure.
It will also be appreciated that certain of the various optional substituents in the compounds of the invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of nitro or halogeno and reduction of nitro. The reagents and reaction conditions for such procedures are well known in the chemical art.
If not commercially available, the necessary starting materials for the above procedures may be made by procedures which are selected from standard techniques of heterocyclic chemistry, techniques which are analogous to the synthesis of known, structurally similar compounds (particularly those described in the above noted EPA publications and their counterparts), and techniques which are analogous to the above described procedures or the procedures described in the Examples below. The starting materials and the procedures for their preparation are additional aspects of the invention.
As will be clear to one skilled in the art, a variety of sequences is available for preparation of the starting materials, and the sequences leading to the starting materials and products of the invention may be altered if appropriate considerations regarding the synthetic methods and radicals present are followed.
The utility of a compound of the invention or a pharmaceutically acceptable salt thereof (hereinafter, collectively referred to as a xe2x80x9cCompoundxe2x80x9d) may be demonstrated by standard tests and clinical studies, including those disclosed in the EPA publications noted above, such as EPA 428434 or EPA 474561 (or U.S. Pat. No. 5,236,921), and those described below.
Neurokinin A (NKA) Receptor-binding Assay (Test A)
The ability of a Compound of the invention to antagonize the binding of NKA at the NK2 receptor may be demonstrated using an assay using the human NK2 receptor expressed in Mouse Erythroleukemia (MEL) cells, as described in: Aharony, D., Little, J., Thomas, C., Powell, S., Berry, D. and Graham, A. Isolation and Pharmacological Characterization of a Hampster Neurokinin A Receptor cDNA, Molecular Pharmacology, 1994, 45, 9-19. In an initial use of this assay, the IC50 measured for the standard compound L-659,877 was found to be 30 nM versus 3H-NKA binding to MEL.
The selectivity of a Compound for binding at the NK2 receptor may be shown by determining its binding at other receptors using standard assays, for example, one using a tritiated derivative of SP in a tissue preparation selective for NK1 receptors or one using a tritiated derivative of NKB in a tissue preparation selective for NK3 receptors.
Guinea Pig Assay (Test B)
The ability of a Compound of the invention to antagonize the action of an agonist, either NKA or [b-ala8]-NKA(4-10), in a pulmonary tissue may be demonstrated using a functional assay in guinea pig trachea, which is carried out in a manner similar to that described in International Patent Application Publication Number WO 94/10146 beginning at pages 19-20.
Clinical studies to demonstrate the efficacy of a Compound of the invention may be carried out using standard methods. For example, the ability of a Compound to prevent or treat the symptoms of asthma or asthma-like conditions may be demonstrated using a challenge of inhaled cold air or allergen and evaluation by standard pulmonary measurements such as, for example, FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity), analyzed by standard methods of statistical analysis.
It will be appreciated that the implications of a Compound""s activity in Test A or Test B is not limited to asthma, but rather, that the test provides evidence of general antagonism of NKA. In general, the Compounds of the invention which were tested demonstrated statistically significant activity in Test A with a Ki of 1 mM or much less. For example, the compound described in Example 2 was found to have a Ki of 23 nM. In Test B, a pKB of 5 or greater was typically measured for a Compound of the invention. For example, a pKB of 8.7 was measured for the compound described in Example 3.
As discussed above, a compound of formula I or a pharmaceutically acceptable salt thereof possesses NKA antagonist properties. Accordingly, it antagonizes at least one of the actions of NKA which are known to include bronchoconstriction, increased microvascular permeability, vasodilation and activation of mast cells. Accordingly, one feature of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of a disease in a human or other mammal in need thereof in which NKA is implicated and antagonism of its action is desired, such as for example the treatment of asthma or a related disorder. In addition, another feature of the invention is provided by the use of a compound of formula I or a salt thereof as a pharmacological standard for the development and standardization of new disease models or assays for use in developing new therapeutic agents for treating the diseases in which NKA is implicated or for assays for their diagnosis. When used in the treatment of such a disease, a compound of the invention is generally administered as an appropriate pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore and a pharmaceutically acceptable diluent or carrier, the composition being adapted for the particular route of administration chosen. Such a composition is provided as a further feature of the invention. It may be obtained employing conventional procedures and excipients and binders, and it may be one of a variety of dosage forms. Such forms include, for example, tablets, capsules, solutions or suspensions for oral administration; suppositories for rectal administration; sterile solutions or suspensions for administration by intravenous or intramuscular infusion or injection; aerosols or nebulizer solutions or suspensions for administration by inhalation; or powders together with pharmaceutically acceptable solid diluents such as lactose for administration by insufflation.
For oral administration a tablet or capsule containing up to 250 mg (and typically 5 to 100 mg) of a compound of formula I may conveniently be used. For administration by inhalation, a compound of formula I will be administered to humans in a daily dose range of, for example, 5 to 100 mg, in a single dose or divided into two to four daily doses. Similarly, for intravenous or intramuscular injection or infusion a sterile solution or suspension containing up to 10% w/w (and typically 0.05 to 5% w/w) of a compound of formula I may conveniently be used.
The dose of a compound of formula I to be administered will necessarily be varied according to principles well known in the art taking account of the route of administration and the severity of the condition and the size and age of the patient under treatment. However, in general, the compound of formula I will be administered to a warm-blooded animal (such as man) so that a dose in the range of, for example, 0.01 to 25 mg/kg (and usually 0.1 to 5 mg/kg) is received. It will be understood that generally equivalent amounts of a pharmaceutically acceptable salt of a compound of formula I may be used.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (xc2x0 C.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25xc2x0 C.;
(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals; 4.5-30 mm Hg) with a bath temperature of up to 60 xc2x0 C.;
(iii) chromatography means flash chromatography on silica gel; reversed phase chromatography means chromatography over octadecylsilane (ODS) coated support having a particle diameter of 32-74 m, known as xe2x80x9cPREP-40-ODSxe2x80x9d (Art 731740-100 from Bodman Chemicals, Aston, Pa., USA); thin layer chromatography (TLC) was carried out on silica gel plates; radial chromatography refers to chromatography on circular thin layer silica gel plates (Analtech) on a Harrison Research Model 8924 Chromatotron.
(iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
(v) melting points are uncorrected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;
(vi) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra;
(vii) yields are given for illustration only and are not necessarily those which may be obtained by diligent process development; preparations were repeated if more material was required;
(viii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulfoxide (DMSO-d6) as solvent; conventional abbreviations for signal shape are used; for AB spectra the directly observed shifts are reported; coupling constants (J) are given in Hz; Ar designates an aromatic proton when such an assignment is made;
(ix) chemical symbols have their usual meanings; SI units and symbols are used;
(x) reduced pressures are given as absolute pressures in pascals (Pa); elevated pressures are given as gauge pressures in bars;
(xi) solvent ratios are given in volume:volume (v/v) terms; and
(xii) mass spectra (MS) were run with an electron energy of 70 electron volts in the electron exposure probe; where indicated ionization was effected by chemical ionization (CI) or fast atom bombardment (FAB); values for m/z are given; generally, only ions which indicate the parent mass are reported.